Method of treating hypertension with morphanthridines

ABSTRACT

THE INVENTIVE METHOD COMPRISES ADMINISTERING A MORPHANTHRIDINE TO A HYPERTENSIVE ANIMAL TO EFFECT A LOWERING OF BLOOD PRESSURE. REPRESENTATIVE OF THE COMPOUNDS THAT CAN BE USED IN THE METHOD ARE 2-CHLORO-11-(3-DIMETHYLAMINOPROPYLIDENE)-MORPHANTHRIDINE AND 11-(1-METHYL4-PIPERIDYLENE)-MORPHANTHRIDINE.

3,786,148 METHOD OF TREATING HYPERTENSION WITH MORPHANTHRIDINES Richard Dage, Brown Deer, Wis., assignor to ColgatelPalmolive Company, New York, N.Y.

No Drawing. Continuation-impart of application Ser. No. 49,502, June 24, 1970, now Patent No. 3,692,906. This application Aug. 3, 1972, Ser. No. 277,527

Int. Cl. A61k 27/00 US. Cl. 424-267 3 Claims ABSTRACT OF THE DISCLOSURE The inventive method comprises administering a morphanthridine to a hypertensive animal to effect a lowering of blood pressure. Representative of the compounds that can be used in the method are 2-chloro-11-(3-dimethylaminopropylidene)-morphanthridine and ll-(l-methyl- 4-piperidylene)-morphanthridine.

RELATED CASES This application is a continuation-in-part of my copending application Ser. No. 49,502, filed June 24, 1970 now US. Pat. 3,692,906.

DESCRIPTION OF THE INVENTION The present invention relates to a method of treating hypertension in animals by administering to the animals a morphanthridine of the formula inwhichZis l] /& or II (,1 to

in which R and R are selected from hydrogen, a lower alkyl of l to 4 carbon atoms such as methyl, ethyl or isopropyl, or a phenyl'lower alkyl of 7 to 13 carbon atoms such as benzyl, phenethyl or phenylisopropyl, or Am is a heterocyclic amino group such as morpholino, pyrrolidino, piperidino, N-lower alkyl piperazino such as N-methyl piperazino, N-phenyl-lower alkyl piperazino such as N-benzyl piperazino and N-(hydroxy-lower alkyl)- piperazino groups such as 4-(fi-hydroxyethyl) piperazino and is a cyclicamino group such as N-lower alkyl-2,3, or -pr p r dy a 2 3 or 4-p p dy r tN- henylw r a y United States Patent 3,786,148 Patented Jan. 15, 1974 2,3 or 4-piperidyl, a N-lower alkyl-2 or 3-pyrrolidyl or a N-phenyl-lower alkyl-2 or B-pyrrolidyl.

In the preferred practice of the invention the hypertensive animal is administered a safe and effective amount of the active ingredient in the form of its free base or in the form of a nontoxic acid addition salt. The active ingredient is preferably combined with one or more pharmaceutical diluents and formed into suitable dosage forms for oral, parenteral or rectal administration.

The compounds employed in the present invention may be conveniently prepared by oxidation of the corresponding 5.6-dihydromorphanthridines with active manganese dioxide.

The described process may be illustrated as follows:

The 5,6-dihydromorphanthridine starting materials may be prepared as described in US. Pats. Nos. 3,267,094 and 3,153,652.

Representative of the compounds which may be employed in the practice of the present invention are the following:

1 1- l-methyl-4-piperidylene -morphanthridine,

2-chl0ro-l 1-( l-methyl-4-piperidylene -morphanthridine,

2-trifluoromethyl-1l-( 1-methyl-4-pip-eridylene) -morphanthridine,

1 l- 1-ethyl-4-piperidylene -morphanthridine,

2-chloro-1 1- 1-ethyl-4-piperidylene -morphanthridine,

2-trifiuor0methyl-1 1-( 1-ethyl-4-piperidylene) -morphanthridine,

l 1-( 1-benzyl-4-piperidylene) -morphanthridine,

l 1- 1-methyl-3-piperidylene) -morphanthridine,

1 1- 1-ethyl-3-piperidylene) -morphanthridine,

1 1- 1-benzyl-3-piperidylene -morpl1anthridine,

1 1-(1-methyl-3 -pyrrolidylene -morphanthridine,

1 1- 1-ethyl-3-pyrrolidylene -morphanthridine,

1 l-( 1-benzyl-3-pyrrolidylene -morphanthridine,

l 1-( l-methyl-3-homopiperidylene -morphanthridine,

l1-( l-ethyl-3-homopiperidylene -morphanthridine,

1 1-( 1-benzyl-3 -homopiperidylene -morphanthridine,

1 1- 3-dimethylaminopropylidene -morphantl1ridine,

2-chloro-1 1- 3-dimethylaminopropylidene -morphanthridine,

Z-trifiuoromethyl-l1-(3-dimethylaminopropylidene)- morphanthridine,

1 1- (3-piperazinopropy1idene morphanthridine,

Z-chloro-l 1- 3-piperazinopropylidene -morphanthridine,

2-trifluoromethyl-1 1- 3-piperazinopropylidene) -morphanthridine,

1 1- 3- (4-hydroxyethylpiperazinopropylidene) morphanthridine,

2-chloro-1 1- [3 4-hydroxyethylpiperazinopropylidene) 1- morphanthridine,

2-trifluoromethyl-1 l- [3- 4-hydroxyethylpiperazinopropylidene) ]-morphanthridine,

1 l- 3-diethylaminopropylidene -morphanthridine,

2-chloro-1 1-(3-diethylaminopropylidene)-morphanthridine,

Z-trifluoromethyl-l 1- 3-diethylaminopropylidene morphanthridine,

11- 3-methylaminopropylidene -morphanthridine,

2-chloro-1 1- 3-methylaminopropylidene) -morphanthridine,

2-trifiuoromethyl-1 1- 3-methylaminopropylidene morpha r tl ridine,

11- 3 -dimethylaminopropyl) -morphanthridine,

Z-chloro-l 1- 3-dimethylaminopropyl -morphanthridine,

8-chloro-1 1-( 3-dimethylaminopropyl -morphanthridine,

Z-trifluoromethyl-l 1-( 3-dimethylaminopropyl) -morphanthridine,

1 1- 3-diethylaminopropyl) -morphanthridine,

2-chloro-1 1- 3 -diethylaminopropyl -morphanthridine,

8-chloro-1 1- 3-diethylaminopropyl -morphanthridine,

2-trifluoron1ethyl-1 1- 3-diethylaminopropyl -morphanthridine,

1 1-( 3-methylaminopropyl) -morphanthridine,

2-chloro- 1 1- 3-methylaminopropyl -morphanthridine,

8-chlor0-1 1- 3-methylarninopropyl -monphanthridine,

Z-trifiuoromethyl-l1-(3-methylaminopropyl)-morphanthridine,

1 1- (N-methyl-N-benzylaminopropyl) -morphanthridine,

2-chloro-1 1-(N-methyl-N-benzylaminopropy1) -morphanthridine,

8-chloro-1 1- (N-methyl-N-benzylaminopropyl) -mor phanthridine,

2-trifluorornethyl-1 1- (N-methyl-N-b enzylaminopropyl morphanthridine,

1 1- (N-methyl-piperazinopropyl -morphanthridine,

2-chloro-1 1- (N -methyl-piperazinopropyl) -morphanthridine,

S-crloro-l 1- (N-methyl-piperazinopropyl) -morphanthriine,

Z-trifiuoromethyl-l 1- (N-methyl-piperazinopropyl morphanthridine,

1 1- 3-(4-hydroxyethylpiperazinopropyl) ]-morphanthridine,

2-chloro- 1 1- 3- (4-hydroxyethylpiperazinopropyl) morphanthridine,

8-chloro-1 1- 3- (4-hydroxyethylpiperazinopropyl) 1- morphanthridine,

Z-trifluoromethyl-l l- [3 (4-hydroxyethylpiperazinopropyl) -morphanthri dine,

1 1- ('N-methyl-4piperidyl -morphanthridine,

2-chloro-1 1- (N-methyl-4-piperidyl) -morphanthridine,

8-chl0ro-1 1- N-methyl-4-piperidyl) -morphanthridine,

Z-trifluoromethyl-l 1- (N-methyl-4-piperidyl -morphanthridine,

1 1- N-benzyl-4- piperidyl -morphanthridine,

2-chloro-l 1- (N-benzyl-4-piperidyl -morphanthridine,

8-chloro-1 1- (N-benzyl-4-piperidyl -morphanthridine,

Z-trifluoromethyl-l 1- (N-benzyl-4-piperidyl) -morphanthridine,

1 1- N-methyl-3-piperidyl -morphanthridine,

2-chloro-1 1- N-methyl-3-pi peridyl) -morphanthridine,

8-chloro-1 1- (N-methyl-3-piperidyl) -morphanthridine,

2-trifluoromethyl-11-(N-methyl-3-piperidyl)-rnorphanthridine,

1 1- (N-ethy1-3 -pyrrolidyl) -morphanthridine,

l l- (N-benzyl-3-pyrrolidyl -morphanthridine,

1 1- N-methyl-3-homopiperidyl -morphanthridine,

Z-trifluoromethyl-l 1- 3- (4-hydroxyethylpiperazinopropylidene) ]-morphanthridine,

1 1- 3 -diethylaminopropylidene -morphanthridine,

2-chloro-l 1- 3-diethylaminopropylidene -morphanthridine,

Z-trifluoromethyl-l 1- 3-diethylaminopropylidene) morphanthridine,

1 1- 3-methylaminopropylidene) -morphanthn'dine,

2-chloro-1 1-( B-methylaminopropylidene) -morphanthridine, and

2-trifluoromethyl- 1 1- 3-methylaminopropylidene) morphanthridine.

The compounds 2-chloro-11-(3-dimethylaminopropylidene)-monphanthridine, ll-(l-methyl 4 piperidylene)- morphanthridine, 11-(3-dimethylaminopropylidene)-morphanthridine, and 11-(3-dimethylaminopropyl)-morphanthridine are representative of the compounds which can be venously in doses of 0.05 to 1.0 mg./kg. of body weight to vagotomized or nonvagotomized cats, which had been anesthetized with sodium pento'bartitol and/ or chloralose, produced pronounced and sustained decreases in blood pressure.

The compounds when evaluated in sodium pentobarbitol anesthetized dogs produced similar results. The test procedure employed included blood pressure measurement from the right femoral artery using a volume-displacement pressure transducer and polygraph. The compound was administered intravenously into the right femoral vein and blood flow was measured by a single channel flowmeter and monitored on a polygraph. The test animals were both vagotomized and nonvagotomized dogs. In the tests the compounds produced dose related decreases in blood pressure.

The pharmaceutical compositions which may be employed are oral dosage forms such as tablets, coated or uncoated, of the immediate or the sustained release type capsules, syrups, elixirs, sterile parenteral solutions, suppositories, or the like.

Representative of suitable pharmaceutical compositions which may be employed in the practice of the invention are the following:

Powders (1), '(2) and 3) are slugged, then granulated, mixed with (4) and (5) and tableted.

Capsules may be prepared by filling No. 3 hard gelatin capsules with the following ingredients:

CAPSULES Mg. (1 Z-chloro-l1-(3-dimethylaminopropylidene) morphanthridine 10 (2) Lactose, U.S.P. -a 200 (3) Starch, U.S.P. 16 (4) Talc, U.S.P 8

The oral route is generally preferred for administering the compounds of this invention. However, other routes of administration such as parenteral may be employed.

In the preferred practice of the invention the patients will receive daily doses of from 5 mg. to 500 mg. of the active ingredient. The doses to be administered to a specific patient will, of course, depend upon many factors, including the patients overall condition, the severity of the hypertension and the level at which the blood pressure is desired to be stabilized. Generally speaking, however, the daily doses will not normally exceed 3 mg./kg. of body weight intraperitoneally. The oral dose will run somewhat higher and the intravenous doses somewhat lower.

The following examples illustrate the preparation of representative compounds which may be employed in the practice of the invention:

EXAMPLE 1 1 1- (3 -dimethylaminopropylidene) morphanthridine To a cooled slurry of 16.4 g. (0.032 mole) of 3-dimethylamiuopropyltriphenylphosphonium bromide hydrobromide in 50 ml. of tetrahydrofuran is added with stirring 0.064 mole of butyl lithium solution. The mixture is stirred 1 hour at room temperature, cooled, and 4.97 (0.029 mole) of ll-morphanthridone in 25 ml. of tetrahydrofuran added dropwise. The solution is stirred for 1.5 hours at room temperature, refluxed for 10 hours, cooled, 20 mlpof water added and the mixture concentrated. The residue is treated with dilute aqueous hydrochloric acid 7.55; N, 8.82. EXAMPLE 2 1 1-(3-dimethylaminopropylidene) morphanthridine Active manganese dioxide g.) is strired and refluxed with 150 ml. of benzene using a water separator. After 4.5 hours, 3.58 g. (0.013 mole) of 11-(3-dimethylaminopropylidene) 5,6 dihydromorphanthridine in a small amount of benzene is added and the suspension stirred and refluxed for 18 hours. The Mn0 is filtered off, rinsed with benzene, the filtrate concentrated, and the residue chromatographed over 150 g. of silica gel and eluted with benzene-diethylamine (40: 1) to yield an oil, 11-(3-dimethylaminopropylidene)morphanthridine, which is identical to the product of Example 1.

EXAMPLE 3 1 1- l-methyl-4-piperidylene) morphanthridine A suspension of g. of active manganese dioxide in 200 ml. of benzene is stirred and refluxed for 2 hours using a water separator. When no more water separates a solution of 4.95 g. of 5,6-dihydro-11-(1-methyl-4-piperidylene)morphanthridine in 50 ml. of benzene is added and the suspension stirred and refluxed for 16 hours. The inorganic material is filtered off, rinsed with benzene, the filtrate concentrated, and the residue chromatographed over SiO gel using a mixture of benzene-methanol (19: 1) as eluent. The appropriate fractions were combined and distilled using a Kugelrohr apparatus to yield 11-(1- methyl-4-piperidiylene)morphanthridine. IR absorption shows a C=N band at 6.20 micron.

AnalysistCalcd. for C H- N (percent): C, 83.29; H, 6.99; N, 9.71. Found (percent): C, 83.55; H, 7.05; N, 9.73.

EXAMPLE 4 2-ch1oro- 1 1- (3-dimethylaminopropylidene) morphanthridine To a stirred refluxing mixture of 400 ml. of benzene and 36 g. of active manganese dioxide is added 8.95 g. of 2-chloro-1 1-( 3-dimethylaminopropy1idene) 5,-6 dihydromorphanthridine and the mixture is stirred and refluxed for 6 hours using a water separator. The Mn0 is filtered oil, the filtrate concentrated, distilled at high vacuum using a Kugelrohr apparatus, chromatographed over 300 g. of SiO gel and eluted with benzene-methanol (9:1), and the appropriate fractions combined and recrystallized from 35 ml. of petroleum ether (B.P. 70) to yield 2 chloro-l1-(3-dimethylaminopropylidene)morphanthridine, M.P. 92-93.

Analysis.--Ca1cd. for C H ClN (percent): C, 73.41; H, 6.16; N, 9.02; Cl, 11.41. Found (percent): C, 73.99; H, 6.24; N, 8.92; Cl, 11.49.

EXAMPLE 5 l l- 3 -dimethylaminopropyl morphanthridine Active manganese dioxide (25 grams) is refluxed with 250 ml. of benzene using a water separator. After 2 hours, 5.3 grams( 0.019 mole) of 11-(3-dimethylaminopropyl)- 5,6-dihydromorphantridine in ml. of benzene is added and the suspension stirred and refluxed for 18 hours. The MnO is filtered 01f, rinsed with benzene, and the filtrate concentrated to yield the crude base. Chromatography over silica gel using benzene-methanol (19:1) as eluent followed by benzene-diethylamine (40:1) affords 11-(3- dimethylaminopropyl) morph anthridine.

Analysis.-Ca1cd. for C H N (percent): C, 81.97; H, 7.97; N, 10.06. Found (percent): C, 82.24; H, 8.31; N, 10.22.

I claim:

1. A method of treating hypertension in animals which comprises the step of administering to a hypertensive animal a safe and effective amount of a compound of the formula References Cited Berg et al., Chem. Abst., vol. 74 (1971), p. 1302311- SAM ROSEN, Primary Examiner 

